Neurotensin (NT) is brain peptide that regulates brain pathways involved in psychosis and in the therapeutic effects of antipsychotic drugs. Converging evidence suggests that the therapeutic effects of current antipsychotic drugs are mediated by stimulation of endogenous NT. Based upon this evidence, it has been proposed that targeting the NT system may be a productive strategy for developing novel antipsychotic drugs. The NT1 receptor has been implicated in NT's antipsychotic effects. Recently developed NT mimetics that enter the brain after peripheral administration and selectively target NT1 receptors have provided excellent tools to investigate this possibility. Preliminary findings from the Principal Investigator's laboratory indicate that these NT1 agonists produce highly robust antipsychotic- like effects in animal models. In some cases the effects of the NT1 agonists are more robust than the effects exhibited by existing antipsychotic drugs. The mechanism underlying these highly robust effects is not known. The research proposed has two broad goals. First to expand on the promising evidence that that NT1 agonists have potential as novel antipsychotic drugs, focusing in particular on exciting preliminary findings that they may have efficacy on cognitive deficits associated with schizophrenia, an area strongly in need of better treatments. This goal will be accomplished by testing the effects of NT1 agonists in a battery of animal models of cognitive deficits that have relevance to schizophrenia. A second goal is to elucidate the brain circuitry underlying the APD-like effects of endogenous NT and exogenous NT1 agonists. Specifically, experiments will test the hypothesis that both exogenously administered NT1 agonists and endogenous NT released in response to existing antipsychotic drugs produce antipsychotic-like effects by activating NT1 receptors located downstream to the site of action of existing antipsychotic drugs in the antipsychosis pathway. This goal will be accomplished via a number of experimental techniques including administering selective NT1 antagonists into candidate brain sites in order to block the effects of an NT1 agonist and of existing antipsychotics in established animal models that are predictive of antipsychotic activity. If confirmed, this would strongly support the rationale for development of NT1 agonists as potential breakthrough antipsychotic drugs that could have advantages relative to existing antipsychotics because they bypass initial elements of the antipsychosis pathway activated by existing antipsychotic drugs. It would also significantly add to our current understanding of the mechanism by which existing antipsychotic drugs work. PUBLIC HEALTH RELEVANCE: Schizophrenia is a debilitating disorder for which current treatments are unsatisfactory. We propose studies aimed at investigating the possibility of developing novel treatments that target neurotensin, a natural chemical in the brain. The proposed experiments may help lead to completely novel and superior treatments for schizophrenia.